Payments specified under a forward contract must be made on the same dates as order payments which they replace treatment 7th march effective 150 mg rulide. If handlers paid producers under contract at different times than producers not under contract medications requiring prior authorization rulide 150mg discount, disorderly conditions might occur medicine identification generic 150 mg rulide mastercard. Final Action In accordance with the 2008 Farm Bill treatment definition statistics rulide 150mg with mastercard, this final rule establishes the dairy forward pricing program medications safe for dogs buy 150mg rulide with amex. These provisions are included in a new part 1145 medications keppra purchase 150 mg rulide amex, which provides separate sections for Definitions medicine zyprexa generic rulide 150mg with amex, Rules Governing Forward Contracts and Enforcement of the program treatment 3rd degree hemorrhoids 150 mg rulide for sale. Subtitle F of Title I of the 2008 Farm Bill at section 1601 provides for an implementation timeframe and the promulgation of the regulations to establish a Dairy Forward Pricing Program without regard to the Paperwork Reduction Act (44 U. Accordingly, these provisions are made final in this action and for the same reasons good cause exists for making this rule effective one day after publication in the Federal Register. To do otherwise would be impracticable, unnecessary, and contrary to the public interest. Printed Name: lllllllllll Signature: lllllllllllll Date: llllllllllllllll Address: llllllllllllll Producer Number: lllllllll (f) Other definitions. The disclosure statement must be signed on the same date as the contract by each producer entering into a forward contract, and this signed disclosure statement must be attached to or otherwise included in each contract submitted to the market administrator. If the handler does not designate the suppliers of the over-contracted milk, the market administrator shall prorate the overcontracted milk to each producer and cooperative association having a forward contract with the handler. A handler may not require participation in a forward pricing contract as a condition of the handler receiving milk from a producer or cooperative association of producers. The investigations conducted on the two helicopters revealed a hydraulic fluid leak from the hydraulic pump casing. In both cases, incorrect position of the liner of the compensating piston had caused the seals to deteriorate. The incorporation by reference of certain publications is approved by the Director of the Federal Register as of December 5, 2008. Relevant Service Information Eurocopter France has issued Emergency Alert Service Bulletin No. This regulation is within the scope of that authority because it addresses an unsafe condition that is likely to exist or develop on product(s) identified in this rulemaking action. Will not have a significant economic impact, positive or negative, on a substantial number of small entities under the criteria of the Regulatory Flexibility Act. This incorrect positioning of the liner is due to noncompliant application of the repair process by a repair station. Material Incorporated by Reference (j) You must use the specified portions of Eurocopter France Emergency Alert Service Bulletin 01. The identified non-compliances were then assessed using Transport Canada Policy Letter No. The assessment showed that supplemental maintenance tasks [for the fuel tank wiring harness installation, and the hydraulic system No. Bombardier Aerospace has completed a system safety review of the aircraft fuel system against fuel tank safety standards * * *. For airplanes that have been previously modified, altered, or repaired in the areas addressed by these inspections, the operator may not be able to accomplish the inspections described in the revisions. The request should include a description of changes to the required inspections that will ensure the continued operational safety of the airplane. We received no comments on the proposal or on the determination of the cost to the public. We estimate the following costs to do the inspection: Parts cost Total cost per airplane $320 Total cost on U. Make all repairs before further flight after the inspection in which scarring or damage is found. If the hole has previously been drilled, the access panel may also be installed in addition to the inspection hole. John Colomy, Acting Manager, Small Airplane Directorate, Aircraft Certification Service. Where the service information lists required parts costs that are covered under warranty, we have assumed that there will be no charge for these parts. As we do not control warranty coverage for affected parties, some parties may incur costs higher than estimated here. Under current European Union regulation, all holders of type certificates for passenger transport aircraft with either a passenger capacity of 30 or more, or a payload capacity of 7,500 pounds (3,402 kg) or more, which have received their certification after January 1st, 1958, are required to conduct a design review against explosion risks. The unsafe condition is the potential of ignition sources inside fuel tanks, which, in combination with flammable fuel vapors, could result in fuel tank explosions and consequent loss of the airplane. The Offshore Airspace Areas listed in this document will be published subsequently in the order. Additionally, the Control 1234L Offshore Airspace area is being modified by lowering the offshore airspace floor to 700 feet above the surface within 6. Interested parties were invited to participate in this rulemaking effort by submitting written comments on the proposal. A contracting state accepting this responsibility may apply the International Standards and Recommended Practices that are consistent with standards and practices utilized in its domestic jurisdiction. In accordance with Article 3 of the Convention, state-owned aircraft are exempt from the Standards and Recommended Practices of Annex 11. Article 3(d) of the Convention provides that participating state aircraft will be operated in international airspace with due regard for the safety of civil aircraft. Since this action involves, in part, the designation of navigable airspace outside the United States, the Administrator has been reviewed by the Secretary of State and the Secretary of Defense in accordance with the provisions of Executive Order 10854. This airspace action is not expected to cause any potentially significant environmental impacts, and no extraordinary circumstances exist that warrant preparation of an environmental assessment. Since this is a routine matter that will only affect air traffic procedures and air navigation, it is certified that this rule, when promulgated, will not have a significant economic impact on a substantial number of small entities under the criteria of the Regulatory Flexibility Act. The purpose of Article 12 and Annex 11 is to ensure that civil aircraft operations on international air routes are performed under uniform conditions. The preamble to the final rule noted that it would not allocate slots to a carrier that was no longer operating at the airport. Bankruptcy Court for the Southern District of Indiana, Indianapolis Division, case no. The provision in the preamble that the air carrier must operate at LaGuardia was directed to the holder of the Operating Authorization under the LaGuardia Order. Under the rule, initial allocation is based on Operating Authorizations allocated under the Order Limiting Operations at LaGuardia Airport (LaGuardia Order) to carriers for the week of September 28, 2008. Specifically, the preamble to the final rule stated: One carrier that held Operating Authorizations in January 2007 is no longer in business, although it continues to hold an air carrier certificate. These slots have been operated under lease agreements by AirTran and Delta Air Lines. That carrier ceased operations at LaGuardia on January 7, 2008, and ceased operations entirely on April 3, 2008. Likewise, these slots would not be considered new or returned capacity that can be reallocated only via auction under 93. Should the total number of common slots exceed 20, the carrier may lose a percentage of the slots in accordance with the final rule. However, depending on when the slots are allocated, reversion of the additional slots may not occur before March, 2010. Availability of Rulemaking Documents You may obtain an electronic copy using the Internet by: (1) Searching the Federal eRulemaking Portal MacPherson, Assistant Chief Counsel for Regulations, Federal Aviation Administration. Therefore, neither an environmental assessment nor an environmental impact statement is required. The supplemental application provides for the veterinary prescription use of firocoxib chewable tablets in dogs for the control of postoperative pain and inflammation associated with orthopedic surgery. Under section 512(c)(2)(F)(iii) of the Federal Food, Drug, and Cosmetic Act (21 U. For the control of pain and inflammation associated with osteoarthritis; and for the control of postoperative pain and inflammation associated with soft-tissue and orthopedic surgery. The Commission will send a copy of this Report and Order in a report to be sent to Congress and the Government Accountability Office pursuant to the Congressional Review Act, see 5 U. To request this document in accessible formats (computer diskettes, large print, audio recording, and Braille), send an e-mail to fcc504@fcc. Provisions of the Regulatory Flexibility Act of 1980 do not apply to this proceeding. The purpose of these notices is to give interested persons an opportunity to participate in the rule making prior to the adoption of the final rules. In this proposed rulemaking, the Department proposes to exempt portions of the system of records from one or more provisions of the Privacy Act because of criminal, civil, and administrative enforcement requirements. Instructions: All submissions received must include the agency name and docket number for this notice. The Privacy Act requires each agency to publish in the Federal Register a description of the type and character of each system of records that the agency maintains, and the routine uses that are contained in each system in order to make agency recordkeeping practices transparent, to notify individuals regarding the uses of their records, and to assist individuals in finding such files within the agency. The Privacy Act allows Government agencies to exempt certain records from the access and amendment provisions. If an agency claims an exemption, however, it must issue a Notice of Proposed Rulemaking to make clear to the public the reasons why a particular exemption is claimed. The exemptions proposed here are standard law enforcement and national security exemptions exercised by a large number of Federal law enforcement and intelligence agencies. In appropriate circumstances, where compliance would not appear to interfere with or adversely affect the law enforcement purposes of this system and the overall law enforcement process, the applicable exemptions may be waived on a case by case basis. Amendment of the records could interfere with ongoing investigations and law enforcement activities and would impose an impossible administrative burden by requiring investigations to be continuously reinvestigated. The Privacy Act embodies fair information principles in a statutory framework governing the means by which the United States Government collects, maintains, uses, and disseminates personally identifiable information. The Privacy Act requires each agency to publish in the Federal Register a description of the type and character of each system of records that the agency maintains, and the routine uses that are contained in each system in order to make agency recordkeeping practices transparent, to notify individuals regarding the uses to which personally identifiable information is put, and to assist individuals in finding such files within the agency. The Privacy Act also allows Government agencies to exempt certain records from the access and amendment provisions. If an agency claims an exemption, however, it must issue a notice of proposed rulemaking to make clear to the public the reasons why a particular exemption is claimed. Disclosure of information to the subject of the inquiry could also permit the subject to avoid detection or apprehension. Providing notice to individuals with respect to existence of records pertaining to them in the system of records or otherwise setting up procedures pursuant to which individuals may access and view records pertaining to themselves in the system would undermine investigative efforts and reveal the identities of witnesses, and potential witnesses, and confidential informants. Disclosure of the accounting would therefore present a serious impediment to law enforcement efforts and/or efforts to preserve national security. Disclosure of the accounting would also permit the individual who is the subject of a record to impede the investigation, to tamper with witnesses or evidence, and to avoid detection or apprehension, which would undermine the entire investigative process. Access to the records could permit the individual who is the subject of a record to impede the investigation, to tamper with witnesses or evidence, and to avoid detection or apprehension. In addition, permitting access and amendment to such information could disclose security-sensitive information that could be detrimental to homeland security. In the interests of effective law enforcement, it is appropriate to retain all information that may aid in establishing patterns of unlawful activity. In addition to new airworthiness standards for transport airplanes and new maintenance requirements, this rule included Special Federal Aviation Regulation No. This requirement applies to type design holders for large turbine-powered transport airplanes and for subsequent modifications to those airplanes. It requires them to perform design reviews and to develop design changes and maintenance procedures if their designs do not meet the new fuel tank safety standards. As explained in the preamble to the rule, we intended to adopt airworthiness directives to mandate any changes found necessary to address unsafe conditions identified as a result of these reviews. In evaluating these design reviews, we have established four criteria intended to define the unsafe conditions associated with fuel tank systems that require corrective actions. The percentage of operating time during which fuel tanks are exposed to flammable conditions is one of these criteria. The other three criteria address the failure types under evaluation: Single failures, single failures in combination with a latent condition(s), and in-service failure experience. For all four criteria, the evaluations included consideration of previous actions taken that may mitigate the need for further action. Replacing the components in the wire assembly of the auxiliary hydraulic pump with new components, and routing the wire assembly installation outside of the tire burst area, will minimize the possibility of wire damage and electrical arcing to the center wing fuel tank. The modification includes replacing the components in the wire assembly of the auxiliary hydraulic pump with new components, and routing the wire assembly installation outside of the tire burst area. The inspections, replacements, wiring changes, and corrective actions specified in Revision 3 of service bulletin are essentially identical to those specified in Revision 2 of the service bulletin. Accomplishing the actions specified in the service information is intended to adequately address the unsafe condition. Costs of Compliance There are about 740 airplanes of the affected design in the worldwide fleet. Required parts would cost about $10,231 or $11,139 per airplane (depending on the kit). The airplane manufacturer states that it will supply required parts to operators at no cost. For certain airplanes, the new proposed action would take about 21 or 23 work hours per airplane depending on the airplane configuration, at an average labor rate of $80 per work hour. This level of inspection is made from within touching distance unless otherwise specified. A mirror may be necessary to ensure visual access to all surfaces in the inspection area. This level of inspection is made under normally available lighting conditions such as daylight, hangar lighting, flashlight, or droplight and may require removal or opening of access panels or doors. Stands, ladders, or platforms may be required to gain proximity to the area being checked. If an improperly functioning passenger oxygen system goes undetected, the passenger oxygen mask could fail to deploy and result in possible incapacitation of passengers during a depressurization event. Action- Modify the generator drive and standby power module assembly in accordance with the Accomplishment Instructions of the Service Bulletin. Modify the air conditioning module assembly in accordance with the Accomplishment Instructions of the Service Bulletin. Ali Bahrami, Manager, Transport Airplane Directorate, Aircraft Certification Service. If left uncorrected, such corrosion could adversely affect the structural integrity of the wing to fuselage joint. You are required to assure the product is airworthy before it is returned to service. The manufacturer has updated the cost of required parts; the required parts now cost up to $24,474 per airplane. This regulation is within the scope of that authority because it addresses an unsafe condition that is likely to exist or develop on products identified in this rulemaking action. The notice of proposed rulemaking would address certain rights granted by a governmental unit that are related to the lease, ownership, or use of toll roads, toll bridges, and certain other physical infrastructure. The notice of proposed rulemaking would address certain rights granted by a governmental unit that are related to the lease, ownership, or use of real property. This document also invites comments from the public regarding these contemplated rules. Further, any asset treated as held by a partner or beneficiary by reason of this rule which is used or held for use by the partnership, trust, or estate in a trade or business is treated as so used or held by the partner or beneficiary. Instead, these taxpayers may take the position that the governmental permit is an asset used or held for use in a trade or business.
Unlike bioinformatics medications voltaren purchase 150mg rulide with visa, whose major focus is the collection and evaluation of existing data symptoms mold exposure purchase rulide 150 mg without prescription, computational biology is experimental and exploratory in nature medications zithromax cheap 150 mg rulide mastercard. By performing virtual experiments and analyses "in silico treatment canker sore cheap rulide 150 mg without prescription," computational biology offers the promise of greatly accelerating the pace and efficiency of scientific discovery symptoms diabetes type 2 buy generic rulide 150 mg. Computational biologists are attempting to develop predictive models that will (1) permit the threedimensional structure of a protein to be determined directly from its primary sequence treatment innovations order 150 mg rulide mastercard, (2) determine the function of unknown proteins from their sequence and structure medicine for the people rulide 150 mg otc, (3) screen for potential inhibitors of a protein in silico medications just like thorazine 150 mg rulide with amex, and (4) construct virtual cells that reproduce the behavior and predict the responses of their living counterparts to pathogens, toxins, diet, and drugs. The creation of computer algorithms that accurately mimic the behavior of proteins, enzymes, cells, etc will enhance the speed, efficiency, and the safety of biomedical research. Computational biology will also enable scientists to perform experiments in silico whose scope, hazard, or nature renders them inaccessible to or inappropriate for conventional laboratory or clinical approaches. Identities with the English word are shown in dark red; linguistic similarities in light red. The major evolutionary question addressed was whether the similarities reflected (1) descent from a common ancestral protein (divergent evolution) or (2) the independent selection of a common mechanism for meeting some specific cellular need (convergent evolution), as would be anticipated if one particular solution was overwhelmingly superior to the alternatives. Calculation of the minimum number of nucleotide changes required to interconvert putative protein isoforms allows inferences to be drawn concerning whether or not the similarities and differences exhibit a pattern indicative of progressive change from a shared origin. Thus, blastp compares an amino acid query sequence against a protein sequence database, blastn compares a nucleotide query sequence against a nucleotide sequence database, blastx compares a nucleotide query sequence translated in all reading frames against a protein sequence database to reveal potential translation products, tblastn compares a protein query sequence against a nucleotide sequence database dynamically translated in all six reading frames, and tblastx compares the six-frame translations of a nucleotide query sequence against the six-frame translations of a nucleotide sequence database. This approach provides speed and increased sensitivity for distant sequence relationships. Input or "query" sequences are broken into "words" (default size 11 for nucleotides, 3 for amino acids). Bioinformatics scientists are developing tools to enable scientists to deduce from the amino acid sequences of unknown proteins their three-dimensional structure and function. Currently, the list of unknown proteins uncovered by genomics contains thousands of entries, with new entries being added as more genome sequences are solved. The ability to generate structures and infer function in silico promises to significantly accelerate protein identification and provide insight into the mechanism by which proteins fold. This knowledge will aid in understanding the underlying mechanisms of various protein folding diseases, and will assist molecular engineers to design new proteins to perform novel functions. The first algorithms used the frequency with which individual amino acids occurred in acids frequently found in -helices, -sheets, turns, and loops to predict the secondary structure topography of a polypeptide. For example, a segment of protein sequence rich in amino -helices was predicted to adopt this conformation. By extending this process, for example, by weighing the impact of hydrophobic interactions in the formation of the protein core, algorithms of remarkable predictive reliability are being developed. However, while current programs perform well in generating the conformations of proteins formed of single domains, projecting the likely structure of membrane proteins and those composed of multiple domains remain problematic. Scientists are also attempting to discern patterns between three-dimensional structure and physiologic function. The shape of the pocket and the distribution of hydrophobic, hydrophilic, and potentially charged amino acids within it can then be used to infer the structure of the biomolecule that binds or "docks" at that site. Compare this model with the backbone representations of proteins shown in Chapters 5 & 6. However, in this case the set of potential ligands to be considered is not confined to those occurring in nature, and is aided by empirical knowledge of the structure or functional characteristics of the target protein. For proteins of known three-dimensional structure, molecular-docking approaches employ programs that attempt to fit a series of potential ligand "pegs" into a designated binding site "hole" on a protein template. To identify optimum ligands, docking programs must account both for matching shapes and for complementary hydrophobic, hydrophilic, and charge attributes. The binding affinities of the inhibitors selected on the basis of early docking studies were disappointing, as the rigid models for proteins and ligands employed were incapable of replicating the conformational changes that occur in both ligand and protein as a consequence of binding, a phenomenon referred to as induced fit (Chapter 7). Imbuing proteins and ligands with conformational flexibility requires massive computing power, however. Shown are three of the many different conformations of glucose, commonly referred to as chair (top), twist boat (middle), and half chair (bottom). Note the differences not only in shape and compactness but in the position of the hydroxyl groups, potential participants in hydrogen bonds, as highlighted in red. Binding affinities for several known inhibitors are compared and contrasted to determine the positive or negative thermodynamic contributions that specific chemical features contribute to ligand binding. This information is used to identify compounds offering the best combination of features. The goal of systems biology is to construct computer models which faithfully reproduce and can predict the behavior of specific functional units that range from the enzymes and metabolites in a biosynthetic pathway to the network of proteins that controls the cell division cycle, to entire cells and organisms. By constructing virtual molecular networks, scientists have been able to determine how cyanobacteria construct a reliable circadian clock using only four proteins. Just as a person constructs a jigsaw puzzle, in part, by surveying the remaining pieces for matches to the gaps in the puzzle, so too scientists can use the gaps encountered in modeling molecular and cellular systems to guide the identification and annotation of the remaining protein pieces. Recently, scientists have been able to successfully create a sustainable metabolic network, composed of nearly two hundred proteins-an important step toward the creation of a virtual cell. The "holy grail" of systems biologists is to replicate the behavior of living human cells in silico. Not only will they permit optimum sites for therapeutic intervention to be identified in a rapid and unbiased manner, but unintended side effects may be revealed prior to the decision to invest time and resources in the synthesis, analysis, and trials of a potential pharmacophore. The ability to conduct fast, economic toxicological screening of materials ranging from herbicides to cosmetics will benefit human health. By manipulating a virtual cell to reproduce the metabolic profile of a patient, underlying genetic abnormalities may be revealed. The interplay of the various environmental, dietary, and genetic factors that contribute to multifactorial diseases such as cancer can be systematically analyzed. Preliminary trials of potential gene therapies can be assessed safely and rapidly in silico. The duplication of a living cell in silico represents an extremely formidable undertaking. Not only must the virtual cell possess all of the proteins and metabolites for the type of cell to be modeled (eg, from brain, liver, nerve, muscle, or adipose), but these must be present in the appropriate concentration and subcellular location. The model must also account for the functional dynamics of its components, binding affinities, catalytic efficiency, covalent modifications, etc. To render a virtual cell capable of dividing or differentiating will entail a further quantum leap in complexity and sophistication. Some promises are at present perceived clearly, others dimly, while yet others remain unimagined. A major objective of computational biologists is to develop computational tools that will enhance the efficiency, effectiveness, and speed of drug development. There seems little doubt that their impact on medical practice in the 21st century will equal or surpass that of the discovery of bacterial pathogenesis in the 19th century. Bioinformatics involves the design of computer algorithms and construction of databases that enable biomedical scientists to access and analyze the growing avalanche of biomedical data. Major challenges in the construction of user-friendly databases include devising means for storing and organizing complex data that accommodate a wide range of potential search criteria. The goal of the Encode Project is to identify all the functional elements within the human genome. Computational biology uses computer algorithms to identify unknown proteins and conduct virtual experiments. Computational biologists are developing programs that will predict the three-dimensional structure of proteins directly from their primary sequence. Computer-aided drug design speeds drug discovery by trying to dock potential inhibitors to selected protein targets in silico. A major goal of systems biologists is to create faithful models of individual pathways and networks in order to elucidate functional principles and perform virtual experiments. The ultimate goal of systems biologists is to create virtual cells that can be used to more safely and efficiently diagnose and treat diseases, particularly those of a multifactorial nature. Bio-logic systems are essentially isothermic and use chemical energy to power living processes. How an animal obtains suitable fuel from its food to provide this energy is basic to the understanding of normal nutrition and metabolism. Death from starvation occurs when available energy reserves are depleted, and certain forms of malnutrition are associated with energy imbalance (marasmus). Thyroid hormones control the rate of energy release (metabolic rate), and disease re-sults when they malfunction. Excess storage of surplus energy causes obesity, an increasingly common disease of Western society, which predisposes to many diseases, including cardiovascular disease and diabetes mellitus type 2, and lowers life expectancy. Biologic Systems Conform to the General Laws of Thermodynamics the first law of thermodynamics states that the total energy of a system, including its surroundings, remains constant. It implies that within the total system, energy is neither lost nor gained during any change. However, energy may be transferred from one part of the system to another or may be transformed into another form of energy. In living systems, chemical energy may be transformed into heat or into electrical, radiant, or mechanical energy. The second law of thermodynamics states that the total entropy of a system must increase if a process is to occur spontaneously. Entropy is the extent of disorder or randomness of the system and becomes maximum as equilibrium is approached. Under conditions of constant temperature and pressure, the relationship between the free-energy change (G) of a reacting system and the change in entropy (S) is expressed by the following equation, which combines the two laws of thermodynamics: where H is the change in enthalpy (heat) and this the absolute temperature. H is approximately equal to E, the total change in in-ternal energy of In biochemical reactions, because the reaction, the above relationship may be expressed in the following way: If G is negative, the reaction proceeds spontaneously with loss of free energy; ie, it is exergonic. If, in G is of great magnitude, the reaction goes virtually to completion and is essentially irreversible. G is positive, the reaction proceeds only if free energy can be gained; ie, it is G is great, the system is stable, with little or no ten-dency G is zero, the system is at equilibrium and no net change takes place. The standard free-energy change the standard free-energy change can be calculated from the equilibrium constant K eq. In a biochemical system, an enzyme only speeds up the attainment of equilibrium; it never alters the final concentrations of the reactants at equilibrium. The conversion of metabolite A to metabolite B occurs with re-lease of free energy and is coupled to another reaction in which free energy is required to convert metabolite C to metabolite D. The terms exergonic and endergonic, rather than the normal chemical terms "exothermic" and "endothermic," are used to indicate that a process is accompanied by loss or gain, respectively, of free energy in any form, not necessarily as heat. In practice, an endergonic process cannot exist independently, but must be a component of a coupled exergonic-endergonic system where the overall net change is exergonic. The exergonic reactions are termed catabolism (generally, the breakdown or oxidation of fuel molecules), whereas the synthetic reactions that build up substances are termed anabolism. One possible mechanism of coupling could be envisaged if a common obligatory intermediate (I) took part in both reactions, ie, Some exergonic and endergonic reactions in biologic systems are coupled in this way. This type of system has a built-in mechanism for biologic control of the rate of oxidative processes, since the common obligatory intermediate allows the rate of utilization of the product of the synthetic path (D) to determine by mass action the rate at which A is oxidized. Indeed, these relationships supply a basis for the concept of respiratory control, the process that prevents an organism from burn-ing out of control. Coupling of dehydrogenation and hydrogenation reactions by an intermediate carrier. The biologic advantage of this mecha-nism is that the compound of high potential energy, unlike I in the previous system, need not be structurally related to A, B, C, or D, allowing E to serve as a transducer of energy from a wide range of exergonic reactions to an equally wide range of endergonic reactions or processes, such as biosyntheses, muscular contraction, nervous excitation, and active transport. Transfer of free energy from an exergonic to an endergonic reaction via a high-energy intermediate compound. Autotrophic organisms utilize simple exergonic processes; eg, the energy of sunlight (green plants), the reaction Fe2+ Fe3+ (some bacteria). On the other hand, heterotrophic organisms ob-tain free energy by coupling their metabolism to the breakdown of complex organic molecules in their environment. Values differ between investigators, depending on the precise conditions under which the measurements were made. High-Energy Phosphates Are Designated by the symbol indicates that the group attached to the bond, on transfer to an appropriate acceptor, results in transfer of the larger quantity of free energy. For this reason, the term group transfer potential, rather than "high-energy bond," is preferred by some. There are three major sources of taking part in energy conservation or energy capture: 1. Oxidative phosphorylation: the greatest quantitative source of in aerobic organisms. Free energy comes from respiratory chain oxidation using molecular O2 within mitochondria (Chapter 12). When (1) and (2) are coupled in a reaction catalyzed by hexokinase, phosphorylation of glucose readily proceeds in a highly exergonic reaction that under physiologic conditions is irreversible. Adenylyl Kinase (Myokinase) Interconverts Adenine Nucleotides this enzyme is present in most cells. Similarly, specific nucleoside monophosphate kinases catalyze the formation of nucleoside diphosphates from the corresponding monophosphates. Exergonic reactions take place spontaneously with loss of free energy (G is negative). Endergonic reactions require the gain of free energy (G is positive) and occur only when coupled to exergonic reactions. This principle of oxidation-reduction applies equally to biochemical systems and is an important concept underlying understanding of the nature of biologic oxidation. Note that many biologic oxidations can take place without the participation of molecular oxygen, eg, dehydrogenations. In addition, molecular oxygen is incorporated into a variety of substrates by enzymes designated as oxygenases; many drugs, pollutants, and chemical carcinogens (xenobiotics) are metabolized by enzymes of this class, known as the cytochrome P450 system. Administration of oxygen can be lifesaving in the treatment of patients with respiratory or circulatory failure. The redox potential of a system (E0) is usually compared with the potential of the hydrogen electrode (0. The relative positions of redox systems in the table allow prediction of the direction of flow of electrons from one redox couple to another. Oxidation of a metabolite catalyzed by an oxidase (A) forming H 2 O, (B) forming H2 O 2. Some Oxidases Contain Copper Cytochrome oxidase is a hemoprotein widely distributed in many tissues, having the typical heme prosthetic group present in myoglobin, hemoglobin, and other cytochromes (Chapter 6). It is the terminal component of the chain of respiratory carriers found in mitochondria (Chapter 13) and transfers electrons resulting from the oxidation of substrate molecules by dehydrogenases to their final acceptor, oxygen. It contains two molecules of heme, each having one Fe atom that oscillates between Fe3+ and Fe2+ during oxidation and reduction. Oxidoreduction of isoalloxazine ring in flavin nucleotides via a semiquinone (free radical) intermediate (center). These dehydrogenases are specific for their substrates but often utilize common coenzymes or hydrogen 1. Since the reactions are reversible, these properties enable reducing equivalents to be freely transferred within the cell. The remaining hydrogen of the hydrogen pair removed from the substrate remains free as a hydrogen ion. They are generally more tightly bound to their apoenzymes than are the nicotinamide coenzymes. Most of the riboflavin-linked dehydrogenases are concerned with electron transport in (or to) the respiratory chain (Chapter 13). Cytochromes May Also Be Regarded as Dehydrogenases the cytochromes are iron-containing hemoproteins in which the iron atom oscillates between Fe3+ and Fe2+ during oxidation and reduction. Except for cytochrome oxidase (previously described), they are classified as dehydrogenases.
The principal difference between this and the previous class symptoms nicotine withdrawal cheap 150 mg rulide fast delivery, apart from the nature of the amino acid to which the oligosaccharide chain is attached (Asn vs Ser or Thr) medications jfk was on generic rulide 150mg with mastercard, concerns their biosynthesis medicine and manicures discount rulide 150mg with mastercard. The presence of the common pentasaccharide is explained by the fact that all three classes share an initial common mechanism of biosynthesis medicine klonopin cheap rulide 150mg. The oligosaccharide branches are often referred to as antennae professional english medicine rulide 150mg without prescription, so that bi- medications vaginal dryness discount rulide 150mg on-line, tri- symptoms tuberculosis rulide 150 mg visa, tetra- symptoms you need a root canal generic rulide 150 mg without prescription, and pentaantennary structures may all be found. High-mannose oligosaccharides typically have two to six additional Man residues linked to the pentasaccharide core. The boxed area encloses the pentasaccharide core common to all N-linked glycoproteins. Schematic diagram of the pentasaccharide core common to all N-linked glycoproteins and to which various outer chains of oligosaccharides may be attached. The sugars of this compound are first assembled on the Dol-P-P backbone, and the oligosaccharide chain is then transferred en bloc to suitable Asn residues of acceptor apoglycoproteins during their synthesis on membrane-bound polyribosomes. To form high-mannose chains, only the Glc residues plus certain of the peripheral Man residues are removed. To form an oligosaccharide chain of the complex type, the Glc residues and four of the Man residues are removed by glycosidases in the endoplasmic reticulum and Golgi. The phenomenon whereby the glycan chains of N-linked glycoproteins are first partially degraded and then in some cases rebuilt is referred to as oligosaccharide processing. Hybrid chains are formed by partial processing, forming complex chains on one arm and Man structures on the other arm. Thus, the initial steps involved in the biosynthesis of the N-linked glycoproteins differ markedly from those involved in the biosynthesis of the O-linked glycoproteins. The former involves Dol-P-P-oligosaccharide; the latter, as described earlier, does not. The process of N-glycosylation can be broken down into two stages: (1) assembly of Dol-P-P-oligosaccharide and transfer of the oligosaccharide; and (2) processing of the oligosaccharide chain. Assembly & Transfer of Dolichol-P-P-Oligosaccharide Polyisoprenol compounds exist in both bacteria and eukaryotic cells. The polyisoprenol used in eukaryotic tissues is dolichol, which is, next to rubber, the longest naturally occurring hydrocarbon made up of a single repeating unit. The phosphate in dolichol phosphate is attached to the primary alcohol group at the left-hand end of the molecule. The reaction is catalyzed by oligosaccharide: protein transferase, a membrane-associated enzyme complex. Only about one-third of the Asn residues that are potential acceptor sites are actually glycosylated, suggesting that factors other than the tripeptide are also important. The dolichol-P can serve again as an acceptor for the synthesis of another molecule of Dol-P-P-oligosaccharide. The thick arrows indicate various nucleotide sugars involved in the overall scheme. In the case of high-mannose glycoproteins, the process may stop here, or up to four Man residues may also be removed. Four external Man residues are removed in reactions 4 and 5 by at least two different mannosidases. To assemble a typical complex oligosaccharide chain, additional sugars must be added to the structure formed in reaction 7. Reactions 9, 10, and 11 involve the addition of Fuc, Gal, and NeuAc residues at the sites indicated, in reactions catalyzed by fucosyl, galactosyl, and sialyl transferases, respectively. Addition of the oligosaccharide to protein occurs in the rough endoplasmic reticulum during or after translation. Removal of the Glc and some of the peripheral Man residues also occurs in the endoplasmic reticulum. The Golgi apparatus is composed of cis, medial, and trans cisternae; these can be separated by appropriate centrifugation procedures. Vesicles containing glycoproteins bud off in the endoplasmic reticulum and are transported to the cis -Golgi. Various studies have shown that the enzymes involved in glycoprotein processing show differential locations in the cisternae of the Golgi. Transfer occurs to specific Asn residues in the sequence AsnX-Ser/Thr, where X is any residue except Pro, Asp, or Glu. The protein-bound oligosaccharide is then partially processed by glucosidases and mannosidases; if no additional sugars are added, this results in a high-mannose chain. Some Glycan Intermediates Formed during N-Glycosylation Have Specific Functions the following are a number of specific functions of N-glycan chains that have been established or are under investigation: (1) the involvement of the mannose 6-P signal in targeting of certain lysosomal enzymes is clear (see above and discussion of I-cell disease, below). Calnexin is a protein present in the endoplasmic reticulum membrane that acts as a chaperone (Chapter 46) and lectin. In this way, calnexin retains certain partly folded (or misfolded) glycoproteins and releases them when further folding has occurred. The glucosyltransferase, by sensing the folding of the glycoprotein and only re-glucosylating misfolded proteins, is a key component of the cycle. This exposes the innermost molecule of glucose, which is recognized by the lectin sites of calnexin and calreticulin. Thus, both the glucosyltransferase and calnexin/calreticulin act as folding sensors. It has been estimated that some 1% of the human genome may be involved with glycosylation events. Multiple species of the other glycosyltransferases (eg, sialyltransferases) also exist. Controlling factors of the first stage of N-linked glycoprotein biosynthesis (ie, oligosaccharide assembly and transfer) include (1) the presence of suitable acceptor sites in proteins, (2) the tissue level of Dol-P, and (3) the activity of the oligosaccharide: protein transferase. Second, there is great interest in analysis of the activities of glycoprotein-processing enzymes in various types of cancer cells. These cells have often been found to synthesize different oligosaccharide chains (eg, they often exhibit greater branching) from those made in control cells. This could be due to cancer cells containing different patterns of glycosyltransferases from those exhibited by corresponding normal cells, due to specific gene activation or repression. The differences in oligosaccharide chains could affect adhesive interactions between cancer cells and their normal parent tissue cells, contributing to metastasis. If a correlation could be found between the activity of particular processing enzymes and the metastatic properties of cancer cells, this could be important as it might permit synthesis of drugs to inhibit these enzymes and, secondarily, metastasis. Some Factors Affecting the Activities of Glycoprotein Processing Enzymes Cell type Different cell types contain different profiles of processing enzymes. Previous enzyme Certain glycosyltransferases act only on an oligosaccharide chain if it has already been acted upon by another processing enzyme. Protein conformation Differences in conformation of different proteins may facilitate or hinder access of processing enzymes to identical oligosaccharide chains. Species Same cells (eg, fibroblasts) from different species may exhibit different patterns of processing enzymes. Cancer Cancer cells may exhibit processing enzymes different from those of corresponding normal cells. The genes encoding many glycosyltransferases have already been cloned, and others are under study. The latter should also cast light on the mechanisms involved in their transcriptional control, and gene knockout studies are being used to evaluate the biologic importance of various glycosyltransferases. Tunicamycin Inhibits N- But Not O-Glycosylation A number of compounds are known to inhibit various reactions involved in glycoprotein processing. These agents can be used experimentally to inhibit various stages of glycoprotein biosynthesis and to study the effects of specific alterations upon the process. For instance, if cells are grown in the presence of tunicamycin, no glycosylation of their normally N-linked glycoproteins will occur. In certain cases, lack of glycosylation has been shown to increase the susceptibility of these proteins to proteolysis. Inhibition of glycosylation does not appear to have a consistent effect upon the secretion of glycoproteins that are normally secreted. In turn, the oligosaccharide chain is linked via phosphorylethanolamine in an amide linkage to the carboxyl terminal amino acid of the attached protein. The functional significance of these variations among structures is not understood. Increased mobility may be important in facilitating rapid responses to appropriate stimuli. Glycation is distinguished from glycosylation because the latter involves enzyme-catalyzed attachment of sugars. When glucose attaches to a protein, intermediate products formed include Schiff bases. These reactions are involved in the browning of certain foodstuffs that occurs on storage or processing (eg, heating). Glucose is shown interacting with the amino group of hemoglobin (Hb) forming a Schiff base. At constant time intervals, the extent of glycation is more or less proportional to the blood glucose level. Thickening of basement membranes can also occur by binding of glycated proteins to them. Damage to renal basement membranes, thickening of these membranes in capillaries and endothelial dysfunction are found in ongoing uncontrolled diabetes mellitus. Non-enzymic attachment of glucose to hemoglobin A present in red blood cells (ie, formation of HbA 1c) occurs in normal individuals and is increased in patients with diabetes mellitus whose blood sugar levels are elevated. As discussed in Chapter 6, measurement of HbA1c has become a very important part of the management of patients with diabetes mellitus. Here, their involvement in two specific processes-fertilization and inflammation -will be briefly described. In addition, the bases of a number of diseases that are due to abnormalities in the synthesis and degradation of glycoproteins will be summarized. Selectins Play Key Roles in Inflammation & in Lymphocyte Homing Leukocytes play important roles in many inflammatory and immunologic phenomena. The first steps in many of these phenomena are interactions between circulating leukocytes and endothelial cells prior to passage of the former out of the circulation. Work done to identify specific molecules on the surfaces of the cells involved in such interactions has revealed that leukocytes and endothelial cells contain on their surfaces specific lectins, called selectins, that participate in their intercellular adhesion. Their amino terminal ends contain the lectin domain, which is involved in binding to specific carbohydrate ligands. The extracellular portion contains an amino terminal domain homologous to C-type lectins and an adjacent epidermal growth factor-like domain. These are followed by a variable number of complement regulatory-like modules (numbered circles) and a trans-membrane sequence (black diamond). The structures of P- and E-selectin are similar to that shown except that they contain more complement-regulatory modules. The initial baseline stage is succeeded by slowing or rolling of the neutrophils, mediated by selectins. These particular interactions are initially short-lived, and the overall binding is of relatively low affinity, permitting rolling. However, during this stage, activation of the neutrophils by various chemical mediators (discussed below) occurs, resulting in a change of shape of the neutrophils and firm adhesion of these cells to the endothelium. The fourth stage is transmigration of the neutrophils across the endothelial wall. For this to occur, the neutrophils insert pseudopods into the junctions between endothelial cells, squeeze through these junctions, cross the basement membrane, and then are free to migrate in the extravascular space. These compounds stimulate various signaling pathways, resulting in changes in cell shape and function, and some are also chemotactic. One important functional change is recruitment of selectins to the cell surface, as in some cases selectins are stored in granules (eg, in endothelial cells and platelets). Sulfated molecules, such as the sulfatides (Chapter 15), may be ligands in certain instances. This basic knowledge is being used in attempts to synthesize compounds that block selectinligand interactions and thus may inhibit the inflammatory response. Approaches include administration of specific monoclonal antibodies or of chemically synthesized analogs of sialyl-Lewisx, both of which bind selectins. Cancer cells often exhibit sialyl-Lewisx and other selectin ligands on their surfaces. It is thought that these ligands play a role in the invasion and metastasis of cancer cells. As mentioned above, many cancer cells exhibit different profiles of oligosaccharide chains on their surfaces, some of which may contribute to metastasis. Some Diseases Due to or Involving Abnormalities in the Biosynthesis of Glycoproteins Cancer Increased branching of cell surface glycans or presentation of selectin ligands may be important in metastasis. It reflects at least in part the presence in the red cell membranes of various glycoproteins with abnormal N-glycan chains, which contribute to the susceptibility to lysis. The absence of fucosylated ligands for selectins leads to a marked decrease in neutrophil rolling. Subjects suffer life-threatening, recurrent bacterial infections and also psychomotor and mental retardation. This latter phenomenon may reflect a slight drop in plasma pH during sleep, which increases susceptibility to lysis by the complement system (Chapter 50). They normally interact with certain components of the complement system (Chapter 50) to prevent the hemolytic actions of the latter. However, when they are deficient, the complement system can act on the red cell membrane to cause hemolysis. It can thus bind agalactosyl IgG molecules, which subsequently activate the complement system (see Chapter 50), contributing to chronic inflammation in the synovial membranes of joints. This is an example of innate immunity, not involving immunoglobulins or T lymphocytes. Deficiency of this protein in young infants as a result of mutation renders them very susceptible to recurrent infections. I-Cell Disease Results from Faulty Targeting of Lysosomal Enzymes As indicated above, Man 6-P serves as a chemical marker to target certain lysosomal enzymes to that organelle. Analysis of cultured fibroblasts derived from patients with I-cell (inclusion cell) disease played a large part in revealing the above role of Man 6-P. I-cell disease is an uncommon condition characterized by severe progressive psychomotor retardation and a variety of physical signs, with death often occurring in the first decade. Cultured cells from patients with I-cell disease were found to lack almost all of the normal lysosomal enzymes; the lysosomes thus accumulate many different types of undegraded molecules, forming inclusion bodies. Samples of plasma from patients with the disease were observed to contain very high activities of lysosomal enzymes; this suggested that the enzymes were being synthesized but were failing to reach their proper intracellular destination and were instead being secreted. Cultured cells from patients with the disease were noted to take up exogenously added lysosomal enzymes obtained from normal subjects, indicating that the cells contained a normal receptor on their surfaces for endocytic uptake of lysosomal enzymes. In addition, this finding suggested that lysosomal enzymes from patients with I-cell disease might lack a recognition marker. Further studies revealed that lysosomal enzymes from normal individuals carried the Man 6-P recognition marker described above, which interacted with a specific intracellular protein, the Man 6-P receptor. It is now known that there are two Man 6-P receptor proteins, one of high (275 kDa) and one of low (46 kDa) molecular mass. It appears that both receptors function in the intracellular sorting of lysosomal enzymes into clathrin-coated vesicles, which occurs in the trans -Golgi subsequent to synthesis of Man 6-P in the cis -Golgi. The low pH in this compartment causes the lysosomal enzymes to dissociate from their receptors and subsequently enter into lysosomes. Only the smaller receptor functions in the endocytosis of extracellular lysosomal enzymes, which is a minor pathway for lysosomal location.
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Westport: Greenwood Press Stewart symptoms 7 buy 150 mg rulide otc, John 1998 Review of Catching Sense: African American Communities on a South Carolina Sea Island by Patricia Guthrie medicine 3605 v purchase rulide 150mg on-line. African American Review 32: 343 Stewart reviews "Catching Sense: African American Communities on a South Carolina Sea Island by Patricia Guthrie lanza ultimate treatment discount rulide 150 mg with visa. Journal of American Folklore 32: 394This small collection of tales focuses on the "deception will be punished" theme which runs through many African/African American stories symptoms bladder cancer order 150 mg rulide fast delivery. Georgia Historical Quarterly 28: 186- 195 Stoddard provides an explanation for the development of the "Gulla" language symptoms zyrtec overdose order rulide 150mg, the merging of African beliefs into Christian concepts symptoms 6dp5dt generic 150 mg rulide mastercard, and the persona presented to the larger world by Negroes of coastal South Carolina and Georgia treatment 4 letter word cheap rulide 150 mg amex. Africa Report 15: (4): 29- 31 Szwed declares that the enslaved Africans mainly from Senegambian and Congo- Angolan regions were able to maintain much of their heritage and that heritage and culture evolved into a form of "Pan- African cultural pattern" that has survived till today medications gerd buy 150mg rulide with visa. South Carolina Historical and Genealogical Magazine 31: 75- 92 Thompson, Robert F. Yale University Press 127, 130- 154 Thornton, John 1993 Central African Names and African- American Naming Patterns. William and Mary Quarterly 50: 727 Naming patterns of Central Africa were evident in South Carolina among Africans brought to the low country. Tobin, Jacqueline 1994 Sweetgrass Basketry: A Cultural Tradition Struggling for Survival. Southern Workman 30 Towne wrote the article on the founding of Penn School shortly before her death. In 1862 when the school began she discusses how it was a learning process for the teachers and the newly freed enslaved people. American Council of Learned Societies 32: 68- 89 1941 Linguistic Research and African Survivals. American Council of Learned Societies 32 National Park Service E49 1945 Notes on the Sounds and Vocabulary of Gullah. Publication of the American Dialect Society 7484 1948 Problems Confronting the Investigator of Gullah. American Dialect Society, Greensboro 74- 84 1958 African Survivals in the New World with Emphasis on the Arts in Africa as Seen by American Negroes. Journal of the Folklore Institute 10: 213- 216 1974 Sources in the Folklore and Folklife of the Sea Islands. Southern Folklore Quarterly 39: 135- 150 Twining states that there is a need to develop a comprehensive collection of Sea Island resources for students interested in studying the history and culture of the islands. She states that some of what is available is biased, some material is beyond the reach of students, and other material is dated. Journal of African Studies: 569- 578 Twining examines present- day historical data on African cultural components in light of the controversy between E. Pleasant region during the early 20th century, and the architecture of the sheds built and used by the women. Journal of Black Studies 10: 449- 460 Twining looks at Negritude within the context of several poems. Shelby State Community College 35- 39 1985 Movement and Dance on the Sea Island Journal of Black Studies 15: 463- 479 According to Twining movement includes games, dance, songs, religious sermons, and speech patterns in storytelling. For Sea Islanders movement is more - it is the person responding to the storyteller, in the relationship between the preacher and the congregation, as well as between the dancer and the audience watching. Journal of Black Studies 10: (4): 379- 386 the blending of African and European cultures on the sea islands and the resultant folkways, language, folklife, and customs are unique in this country. Research needs to determine African connections so that cultural origination points are identified. Journal of Black Studies 10: 387- 416 Twining and Baird present an overview of the sea islands - their history, location, economics, language, religion, and different people create a region which is found nowhere else in the United States. Southern Exposure 5: 161- 165 Vlach provides a cultural and historical framework to explain the African burial practices still being observed among African Americans including the importance of providing the deceased with a proper funeral, the wake or sitting up custom, and the placing on the grave of items used by and of importance to the deceased person. Norton & Company Wade- Lewis, Margaret 1991 Lorenzo Dow Turner: Pioneer African- American Linguist. The Black Scholar 21: 10 A detailed account of the development of "Africanisms in the Gullah Dialect" and its 17 year history collecting material, interviewing Africans in Europe, interviewing Gullah African Americans, and living and working in Africa, Brazil, and England. Bulletin Historical Medicine 65: 185- 208 Wailoo details the early history of the identification of sickle cell anemia as a specific disorder. Journal of American Folklore 7: 318319 Described as "grotesque" Waring gives examples of South Carolina Negro burial customs. She provides anecdotes to support her belief that Africans and African Americans are afraid of dead people and this is reflected in their burial customs. Arts and Activities 84:4 Weintraub, Boris 1984 Just An Incredible Country We Live In. National Wildlife 31: 38- 41 Developers and homeowners building near and over what had been marsh are closing off and eliminating the sweetgrass which is used in basket making forcing the basket makers to go farther away to get the necessary grass. Journal of American Folklore 75: 311- 325 Whitten focuses on North Carolina; he also includes research by Melville Herskovits, African sources of occultism among African Americans, and direct references to South Carolina and the use of the occult in South Carolina. Journal of American Folklore 14: 205- 206 Work, Monroe 1905 Some Geechee Folklore. Southern Workman 35: 633- 635 these examples of folk beliefs include proverbs, animal beliefs, plant superstitions, and miscellaneous beliefs. South Caroliniana Library, University of South Carolina Yates, Irene 1946 Conjures and Cures in the Novels of Julia Peterkin. Southern Folklore Quarterly 10: 137- 149 1947 A Collection of Proverbs and Proverbial Sayings from South Carolina Literature. Southern Folklore Quarterly 11: 187- 199 Yates, Norris 1951 Four Plantation Songs Noted by William Cullen Bryant. Repositories the major portion of information about the Gullah people in South Carolina can be found in the libraries, societies, and collections listed below. Helena Island and Penn Center is located at the University of North Carolina not at Penn Center. Avery Research Center houses information about the urban Gullah culture of Charleston. In addition to papers, books, manuscripts, and audio/visual materials there are collections of artifacts such as baskets, quilts, and other items created by Gullah people. These items are kept as parts of collections of folk traditions representing South Carolina, Africans in America, and testaments to the creativity people existing in extreme circumstances of enslavement created. Scrapbooks of musical transcriptions of black spirituals and street cries are also in the collection. Heyward, Jane DuBose 1882- 1939 In the Heyward papers are poetry written in the Gullah dialect and Gullah stories. Jane DuBose Heyward gave public readings in Gullah as a "dialect recitalist" and she was the mother of Dubose Heyward who wrote the novel "Porgy". Additional novels about the Gullah people, sea island life, and other subjects are included. Helena Island: versions of folk tales, songs, riddles, superstitions, and spirituals are included. It is extremely important to use sites that are connected to libraries, repositories, universities, colleges, governmental agencies, and reputable connectors. There is much information about African Americans and the Gullah that is racist, inflammatory, derogatory, and historically inaccurate. National Park Service E55 E56 Low Country Gullah Culture Special Resource Study Appendix F: Overview and Synthesis of Scholarly Literature by Melissa D. Hargrove Preface Anyone who has recently visited the Sea Islands will realize there is not a minute to spare. There are strip malls where basket stands have stood for half a century or more, which once nourished and sustained the community of Mt. Hilton Head Island is unrecognizable as the agricultural homeland of Gullah people for centuries prior to its devastation. Johns Island has become the red carpet rolled across for tourists on their trek to the gated communities of Kiawah and Seabrook. Gullah residents of Daufuskie Island can hardly even be counted as a community, since their displacement to the periphery of their island home to make way for golf courses and tourism. Helena Island, which has held on for dear life under the constant threat of encroachment, is constantly battling construction permits and development schemes that threaten to strip them of their homes, their heritage, and their cultural legacy. With every hotel that is built and every road that is widened we lose a piece of the history and heritage of the Gullah people. As scholars, activists, government agencies, and inhabitants, we must begin to take steps toward the preservation of this cultural legacy before it is too late. National Park Service F1 Chapter 1 Introduction to the Sea Islands: History, People, and Current Predicaments the Sea Islands are a site of intrigue and wonderment. The landscapes are picturesque, with moss covered live oaks draping the ground in every direction, and seascapes nothing less than breathtaking. But what is truly amazing is the story of the people who were brought to these islands in chains, first from the West Indies and later from Africa. These enslaved souls, and those who have descended from them, are referred to as the Gullah and Geechee of the South Carolina and Georgia Sea Islands. Their history reads like a tragedy, while their strength and courage inspire all who have been fortunate enough to interact with them. The Gullah and Geechee have been objects of academic study for more than a century. Scholars from a variety of academic disciplines have studied every aspect of Gullah culture at different times and using different techniques, but there are overarching themes to the body of literature. Language, religion, verbal arts and folklore, land, health and medicine, arts and crafts, leadership patterns, Gullah worldview and cultural values, and development and change will be utilized as topical categories. Operating from such a framework, it is my sincerest goal to illustrate the significant themes of Gullah scholarship historically and contemporarily. Much of the historical literature will only be used within this overview when necessary for placing complementary research within a broader contextual framework. Historic documentation is necessary, however, more relevant to the issue at hand is research that has required extensive fieldwork within the various Sea Island communities and interaction with those who live and breathe this culture. Introduction the Sea Islands are a string of islands that, geographically, extend from Georgetown, South Carolina to Cumberland Island, Georgia. The adjoining mainland for thirty miles inland is also recognized as part of the Gullah/ Geechee area. The broader discourse of Gullah studies often cites Florida as included within the culture areas; however, there is no significant scholarly data that represent Gullah 1 people occupying Florida Sea Islands. This gap should be considered within any future studies aimed at a comprehensive approach to Sea Island research. As a cultural area, the Sea Islands of South Carolina and Georgia have served as home to the Gullah and Geechee. Geechee is recognized as the term used to refer to Georgia Gullah populations, but the blanket term Gullah can be used to designate all communities descended from Africans who have historically inhabited these Sea Islands. Helena Island, Hunting Island, Fripp Island, Parris Island, Hilton Head Island, and Daufuskie Island. The Georgia Sea Islands, also known as the Golden Isles, consist of: Tybee Island, Skidaway Island, Ossabaw Island, St. Helena Island of South Carolina, as well as Sapelo Island of Georgia, can still declare the existence of a recognizable, cohesive, and viable Gullah/Geechee community (Hargrove 2000). These islands can be classified as low- lying; this area is often referred to as the "Lowcountry," separated from the mainland by small inlets, tidal creeks, and grass- covered marshlands. The islands possess a warm marine environment rich with various types of tropical and subtropical vegetation (Salter 1968). Beneficial to these islands is their extremely long growing season: from 250 to 300 days a year (Salter 1968). The sandy- loam soil of the Sea Islands is well suited to many types of agricultural production, which made them ideal for the plantation economies of rice, indigo and cotton, all of which fed the need for enslaved labor. West Africans seemed the best choice for such a labor force, due to their superior knowledge of rice and indigo cultivation (Schwalm 1997). Those captive F2 Low Country Gullah Culture Special Resource Study Africans, which we now know as the Gullah, forged a common culture out of their shared misery and will to survive and surmount obstacles. It is indeed the entire chain of Sea Islands that became home to hundreds of thousands of enslaved Africans, but the islands of South Carolina are believed to have retained the most sizeable population directly descended from enslaved Africans (Creel 1988). Many scholars maintain that the Sea Islands of South Carolina are the most authentic source of African culture history in North America, due to the overwhelming existence of "Africanisms" (Turner 1949; Guthrie 1996; Pollitzer 1999). Extensive study of the existing literature suggests more research has been conducted in South Carolina Sea Island communities than in Georgia Sea Island communities. Among the earliest English settlers to the Sea Islands were several families from Barbados, already familiar with the system of plantation slavery and the utilization of African labor (Johnson 1930; Schwalm 1997). These first West Indian planters brought close to a thousand laborers with them (Creel 1988). Helena, but moved on to Charles Town upon hearing of the better soil conditions there (Johnson 1930). Charles Town became the major docking point for incoming African captives who were sold in the slave market, which now serves as a tourist attraction in present- day Charleston, South Carolina. It was not until 1700 that the first birth of a Euro American child was reported (Johnson 1930). This event has come to signify the beginning of the colonization of the Sea Islands. Within the literature there are ongoing controversies concerning the origins of enslaved Africans who we now recognize as Gullah and Geechee. The most comprehensive study, to date, appears in the recently published work of William S. The results can be broken down as follows: 39 percent came from Angola (which includes the Congo), 20 percent from Senegambia, 17 percent from the Windward Coast, 6 percent from Sierra Leone, and 13 percent from the Gold Coast (Pollitzer 1999). However, 23,033 (20 percent of the total number of slaves legally imported into South Carolina) were omitted from these calculations because their specific regional origins were not recorded. What developed is a syncretic, creolized culture which was constructed out of a remodeling of various cultural traits brought across the sea from many different parts of West Africa (Mintz and Price 1992), with subsequent influences from European and indigenous sources. This process happened throughout the African Diaspora in locations where slavery became the principle economic strategy for colonial expansion (Mintz and 3 Price 1992). Therefore, there are evident and well established linguistic, cultural, and religious connections between the Caribbean and the Gullah and Geechee people of North America. Establishing the connection between the Caribbean and Gullah/Geechee culture area is an important endeavor, which will "highlight its differences from the rest of the American South" (Montgomery 1994a, 8) as well as expound on "the diversity of Lowcountry culture" (ibid, 14). One of the significant aspects of the Gullah/Geechee- Caribbean connections is the demography of the first Carolina colonies. The first enslaved Africans to work the soil of South Carolina were transplanted there from Barbados and Jamaica (Cassidy 1994). Cassidy, speaking from a linguistic standpoint, suggests that the striking similarities among the Creole languages of the Caribbean and the Sea Islands cannot be accidental (1994, see also Hopkins 1992). For example, Beckwith (1924) uncovered the links between them through trickster tales, best illustrated by the presence of Anansi stories in the Caribbean and South Carolina (which ultimately connects both areas, culturally, to West Africa). The folklore collection of Parsons (1923) also reveals similarities between the Caribbean (particularly the Bahamas) and the Gullah area. National Park Service F3 Religious connections between the Caribbean area and the Gullah/Geechee area are most easily understood in terms of syncretism. Syncretism, defined as the blending of differing systems of belief, is appropriate in terms of establishing a connection between religious belief and practice in these particular Diasporas. Gullah spiritual beliefs represent the syncretism of Christianity and African religion (Butler 1975; Creel 1988; Hart 1993; Pollitzer 1999). Gullah religion will be further discussed in subsequent chapters; however, it is important to reveal its similarities to syncretic religions of the Caribbean area, such as Voodoo of Haiti (also spelled Vodou and Vodun) and Santeria of Cuba (Jones- Jackson 1994). Santeria was created in Cuba by the earliest Yoruba slaves as it was blended with the Catholic belief system of the Spanish. The idea of one God (or higher power) was comparable to African belief systems (Jones- Jackson 1994). Also, the worship of saints in Catholicism had distinct parallels with Orisha worship in Yoruba culture. Spirit possession, documented within Gullah culture ("falling out" Twining 1977), Voodoo, and Santeria is yet another connection between the Gullah and Caribbean syncretic belief systems. An entire volume could be written on the cultural connections between the Caribbean and the Gullah/Geechee area; however, the scholarly literature documenting such connections lacks synthesis, and should be of consideration in the future. What can be definitely established is the shared experiences of enslaved Africans (Mintz and Price 1992) both in the Caribbean and the Sea Islands. These groups shaped a creolized culture out of traits from Africa, interactions with Europeans, Indigenous peoples, and residents of the established slave populations they joined in the New World. Cultural connections, religious connections, and linguistic connections between the Caribbean and the Gullah/ Geechee community establish the need for increased research in the area referred to as "Africanisms. There are many such "Africanisms" within the various elements of Gullah culture, including songs, folklore, games, language, musical instruments, basketry, crafts, woodworking, initiation ceremonies, and herbal plant usage for healing purposes. Those who came from the Guinea Coast are credited with contributions in the areas of grammar, magic, secret societies, possession and trance, quilting, ceramics, and skilled metallurgy (Pollitzer 1999). The Central African captives brought many Bantu words and names, as well as values of kinship and their deep religious beliefs concerning death and the afterlife (Creel 1990; Pollitzer 1999). As Pollitzer illustrates through many years of study, "no one sea island can be connected to a specific region in Africa" (1999, 198). What can be alleged with relative certainty, however, is that Gullah culture is an amalgamation of many different cultural elements from West and Central Africa. Etymology of "Gullah" and "Geechee" There are two dominant hypothetical accounts on the etymology of the word "Gullah. Another possibility is a derivation of "Gola," sometimes spelled Goulah, which refers to a large group of Africans from Liberia who were heavily imported into the Sea Islands at the height of rice and indigo cultivation (Wood 1975; Creel 1988). Less scholarly work has been conducted on the origin of "Geechee," however a number of scholars suggest the term is derived from the Ogeechee River area of Georgia (Sengova 1994). Transitions: From Slavery to Freedom It was November of 1861 when the guns of "big shoot" rang out through Port Royal Sound. As Union armies invaded the areas inland of the island plantations, the white owners fled leaving everything just as it was in the hopes of soon returning. Those who had a chance informed the overseers of the situation, assuring them they would return; those without time left their slaves behind with no warning of what was to come.
Subunit Activation of G-Protein the inactive G protein is a trimer with alpha medications zyprexa discount 150 mg rulide, beta and gamma subunits medicine man gallery discount rulide 150 mg line. Mechanism of Action of Some Toxins Cholera toxin is encoded by a bacteriophage present inside the bacteria Vibrio cholerae treatment 7th march order rulide 150mg with visa. The A subunit then enters into the inner part of the membrane medicine and technology purchase 150mg rulide mastercard, which leads to ribosylation of the alpha subunit of Gs protein medicine xarelto order 150mg rulide with mastercard. This prevents absorption of salts from intestine leading to watery diarrhea and loss of water from body medications pancreatitis cheap 150mg rulide mastercard. Hyperactivity of these channels will result in loss of sodium chloride with watery diarrhea (liquid stools) treatment zinc toxicity purchase 150 mg rulide with visa, that may have fatal results medications 4 times a day buy generic rulide 150mg on-line. Effects of bacterial toxins from Clostridium tetani are exerted through proteases, that attack proteins involved in synaptic vesicle and plasma membrane fusion. The toxin has two polypeptides, one of which binds to cholinergic motor neurons and facilitates the entry of the second polypeptide. Failure to release the neurotransmitter leads to fatal paralysis of the chest muscles. Chapter 44; Mechanisms of Action of Hormones 523 amplification effect is seen in this series of activation reactions. A summary of the cascade activation of enzymes by the hormone is shown in Figure 44. There are Many G-Proteins About 30 different G-proteins are identified, each being used for different signal transduction pathways. The G protein, which stimulates adenyl cyclase, is called Gs (G stimulatory) and the opposite group is called Gi (G inhibitory). The alpha subunit of the Gs and Gi are different, but beta and gamma are the same. G proteins are also involved in toxic manifestations of cholera and pertussis (Box. Hepatic Protein Phosphatase-1 is a typical example where the enzyme itself is inhibited by phosphorylation of its regulatory subunit. Protein kinases as well as protein phosphatases are involved in the action of different hormones. Activation of Protein kinase and phosphorylation of effector proteins like enzymes and ion channels. These enzymes may directly phosphorylate enzymes or secondary kinases that phosphorylate other enzyme. When ion channel proteins or transporters are phosphorylated, the membrane potential is modified, thus regulating the influx of calcium. The termination of the effect of the hormonal action by phosphorylation is effected by the action of protein phosphatases. Calcium Based Signal Transduction Calcium is an important intracellular regulator of cell function like contraction of muscles, secretion of hormones and neurotransmitters, cell division and regulation of gene regulation. The intracellular calcium concentration is low (10-7) whereas extracellular calcium concentration is very high (10-3), maintaining a 10,000 fold calcium gradient across the membrane. Even small increase in cytosolic free calcium can have maximal effect on calcium regulated cellular functions. When cytosolic calcium increases, binding regulatory proteins, activation of several calcium binding regulatory proteins occurs. Calmodulin is expressed in various tissues and mediates the regulatory actions of calcium ions. Calmodulin, the calcium dependent regulatory protein within the cell has four calcium binding sites. When calcium binds there is a conformational change to the calmodulin, which has a role in regulating various kinases. Calmodulin is a 17 kDa protein which has structural and functional similarity with the muscle protein troponin C. The binding of hormones like serotonin to cell surface receptor triggers the activation of the enzyme phospholipase-C which hydrolyses the phosphatidyl inositol to diacylglycerol. The elevated intracellular calcium then triggers processes like smooth muscle contraction, glycogen breakdown and exocytosis. There is "cross talk" between the various signal transduction pathways that are co-ordinately regulated. The enzymes are thus activated, even at physiological levels of calcium within the cell. These include drugs like nitroprusside, nitroglycerine, sodium nitrite and atriopeptides (a group of peptides produced by atrial cardiac tissue). All these compounds act as potent vasodilators, by inhibiting the phosphodiesterase. They diffuse through the plasma membrane and bind to the receptors in the cytoplasm. Each monomer binds to a single steroid molecule at a hydrophobic site, but on binding to genes they dimerise. Steroid hormones influence gene expression, so that the rate of transcription is increased. Steroid receptors have been found to enhance initiation of transcription by formation of complexes at promoters. Insulin Signaling Pathway Insulin acts by binding to a plasma membrane receptor on the target cells. This binding activates the tyrosine kinase activity of the beta subunit, leading to auto-phosphorylation of the beta subunit. This leads to transcription of specific genes for key enzymes of glycolysis, such as glucokinase. This pathway leads to increased synthesis of glucose transporters, insulin receptors, etc. Janus is a Greek mythological figure with two heads; the name is given because Jak dimerises. The name for the month of January is also derived from this Janus; January faces both the previous and present year). It binds to various gene promoters and activates transcription of proteins involved in inflammatory response. Related Topics Insulin and glucagon (Chapter 24); adrenalin and noradrenalin (Chapter 17); renin, angiotesin (Chapter 30); calcitriol (Chapter 33); parathyroid hormone and calcitonin (chapter 35). Gonadotropins Hypothalamic and Pituitary Hormones active molecule, and then transported to posterior pituitary and stored there. Hypernatremia and hypertonic contraction of extra the hypothalamus produces two types of endocrine factors; (a) the hypothalamic neuropeptides and (b) the hypothalamic releasing factors. The releasing factors are inhibitory neuro-secretions synthesized in the hypothalamus and released through the hypothalamic pituitary portal circulation. Long and short loops of feedback Chapter 45; Hypothalamic and Pituitary Hormones 529 Table 45. The secretion of hormones by adenohypophysis or anterior pituitary is under the control of peptides secreted by hypothalamus. Several peptides having effects on anterior pituitary, either stimulant (releasing factors), or inhibitory, have been identified. The secretion of the hypothalamic peptides are also under the feedback control of anterior pituitary tropic hormones (short loop feedback) as well as the target gland hormones (long loop feedback). Secretions of all these hormones are under the control of hypothalamic releasing or inhibitory factors. Slow onset is mostly asymptomatic and goes unnoticed but those with acute onset will manifest the symptomatology of water intoxication (headache, confusion, anorexia, nausea, vomiting, coma and convulsions). Suckling generates a neurogenic reflex, which stimulates the production of oxytocin. It causes contraction of the myo-epithelial cells expelling the milk into milk ducts from the acini. Abnormalities of gonadotropin Male Prepubertal deficiency Postpubertal deficiency Failure to attain puberty. No secondary sexual characteristics Infertility, loss of libido, impotence testicular failure Precocious puberty Female Failure to attain menarche Infertility, amenorrhea, ovarian failure Precocious puberty. They are responsible for increasing the threshold of pain, especially under conditions of stress. Morphine binds to the receptors for endorphins, by which morphine induces the pain relief. The alpha unit is common to all the three, while the beta subunit is specific for each of them. Decreased levels are observed in primary hyperthyroidism, secondary hypothyroidism (pituitary origin), tertiary hypothyroidism (hypothalamic), subclinical hyperthyroidism. This condition is typically manifested in males as failure in production of normal numbers of sperm. Lactotrops hyperplasia is induced by estrogen (during last two trimesters of pregnancy). Prolactin Suppression Test by L-Dopa: Failure to respond to L- dopa indicates autonomous function of pituitary prolactin secreting cells. Cholesterol is first acted upon by desmolase and a 6-carbon unit is cleaved off, forming the 21 carbon steroid, pregnenolone. The beta hydroxyl group is converted to a keto group by a 3-beta-ol-dehydrogenase and the 5 double bond shifted to 4. The major adrenal glucocorticoids are cortisol, cortisone and corticosterone in that order. The major mineralocorticoid is aldosterone, but 11deoxy-corticosterone and corticosterone also have significant mineralocorticoid activity. The adrenal cortex has three different zones each responsible for production of different classes of steroid hormones (C21, C19 and C18). The smallest and outermost zona glomerulosa produces the C21 steroids, mineralo-corticoids. The middle zone of the adrenal cortex, the zona fascicularis produces the glucocorticoids mainly; and adrenal androgens and estrogens to a lesser extent. Cortisone was isolated by Tadeus Reichstein; the structure was identified by Edward Kendall, while Philip Hench in 1948 showed its. The level of aldosterone is also affected by position, highest values in upright posture and lowest while lying down. All steroid hormones act through intracellular messengers and increase the rate of transcription. About 20% is bound to albumin and the rest is free, which is the biologically active fraction. The C21 steroids are reduced to their tetrahydro derivatives, which are excreted as their glucuronides or sulfates in urine. The urinary steroids are referred to as 17-ketosteroids and 17-hydroxy steroids (see structure in Figure 46. The 17-ketosteroids may be derived from both adrenal steroids and androgens from the gonads. Summary of major pathways for production of glucocorticoids, mineralocorticoids and sex steroids. Precursors in red box; intermediaries in grey box; hormones in blue box; excretory products in brown box Assessment of Glucocorticoid Secretion 1. Estimation of urinary free cortisol the free cortisol in plasma is the biologically active fraction. Synthesis of sex hormones 11-oxygenation index is a measure of adrenal steroid production since 11-hydroxylation occurs only in adrenal cortex. The 17-hydroxy steroids are directly derived from the adrenal steroids (glucocorticoids and mineralocorticoids). The term 17-ketogenic steroids is used to include all the compounds having a keto or hydroxyl group at 17th carbon. Biological Effects of Glucocorticoids the glucocorticoids, as the name suggests, mainly affect metabolism of glucose. There is excessive production of adrenal androgens, leading to virilism and hirsutism. Structural difference between 17-hydroxy and 17-ketosteroids (Only the D ring of structure is shown) 4. In normal people, the overnight suppression with low dose (2 mg) causes a 50% fall in the original value. Since the 24-hour excretion is measured, the diurnal variation is also taken care of. Estimation of 17 ketosteroids in urine is often very useful in observing the response of patients to suppression and simulation tests as well as to assess the effectiveness of replacement therapy. Hence alternate pathways of sex steroids are more operative and the urinary excretion of 17-ketosteroids tends to elevate. Increase lipid mobilization; facilitate lipolytic hormones leading to hyperlipidemia. Decrease serum calcium by inhibiting osteoblast function, leading to osteoporosis. Lipids Proteins and nucleic acids Fluid and electrolytes Bone and calcium Secretory action Connective tissue Immune system 536 Textbook of Biochemistry; Section F: Hormones Table 46. This would result in virilization of female children who develop ambiguous genitalia. Drugs increasing the levels of aldosterone are angiotensin, estrogens, laxatives, loop diuretics, metoclopramide, oral contraceptives, potassium, sodium restriction, spironolactone and thiazide diuretics. Drugs decreasing the levels are angiotensin converting enzyme inhibitors (captopril, enalapril, linsinopril, glutethemide, deoxy corticosterone, prolonged heparin therapy, indomethacin, saline and saralasin. Adolf Butenandt isolated estrogen (1929), progesterone (1934) and testosterone (1935), for which he was awarded Nobel prize in 1939. These are converted to C18 estrogens by granulosa cells, by aromatization of ring A and loss of C19 methyl group. Estradiol has not only a critical impact on reproductive and sexual functioning, but also affects other organs including the bones. Estradiol enters cells freely and interacts with a cytoplasmic target cell receptor. Under the influence of estrogen, uterine endometrium proliferates, glands in endometrium are hypertrophied, ducts in mammary gland are proliferated and progesterone receptors are synthesized. Under the influence of progesterone, endometrium enters the secretory phase, and prepares for implantation of the fertilized ovum. If implantation has not occurred, hormone levels are decreased and the secretory glands of the endometrium are denuded. Clomiphen citrate competes with estrogen for receptors in hypothalamus, thus removing the feedback inhibition. Certain breast cancers, especially in perimenopausal women are estrogen-dependent. In such patients, estrogen receptor antagonists (Tamoxifen) will block the estrogen receptors, and cancer cells tend to die. In humans, testosterone is the major male hormone, while in animals, it is androstenedione. Thus high concentration of androgen is made available locally at the seminiferous tubules, at the site of spermatogenesis. Androgens stimulate spermatogenesis, produce hypertrophy of prostate, seminal vesicles, muscle, bone and kidney cells. Fenasteride can inhibit 5-alphareductase, and hence it is used as a treatment for prostate hypertrophy. The program of iodination of common salt has resulted in increased availability of iodine. Ingredients in foodstuffs, which prevent utilisation of iodine are called goitrogens. Goitrogens are seen in cassava, maize, millet, bamboo shoots, sweet potatoes and beans. The only biological role of iodine is in formation of thyroid hormones, thyroxine (T4) and tri-iodo thyronine (T3). Synthesis and Secretion of Thyroxine Step 1, Uptake of Iodine Thyroid gland takes up and concentrates iodine (Step 1 in. The congenital defect, iodine trapping defect, may be treated by large doses of iodine. Step 2, Oxidation of Iodine the iodide taken up by the thyroid cell is oxidised to active iodine (Step 2 in. In patients with an inborn error of iodide oxidation defect, treatment is T4 administration. There are 115 tyrosine residues in the Tgb, out of which 35 residues can be iodinated. Iodination of the tyrosine is taking place on the intact Tgb molecule in the follicular space. Step 4, Coupling Some of the tyrosine residues in the thyroglobulin are aligned opposite each other, and are coupled (step 4. The iodination and coupling are taking place in the borders of the follicular cells. Step 5, Storage the thyroid gland is unique, in that it is the only endocrine gland to store appreciable amounts of the hormone (Step 5 in. Step 6, Utilization When necessity arises, the thyroglobulin is taken from the acinar colloid, into the cell by pinocytosis (Step 6. This hydrolysis is depressed by iodide and therefore potassium iodide (Kl) is used as an adjuvant in hyperthyroidism.
